Tablet structure



g-v 96 G. KRAUSEY ETAL 3,336,200

TABLET S TRUCTURE Filed Ocit. 1, 1963 INVENTORS:

FRED C. NINGER GEORGE M. KRAUSE ATTORN EY United States Patent Thisapplication is a continuation-in-part of application Ser. No. 150,000,filed Nov. 3, 1961, and now abandoned.

The present invention relates to a method for the preparation of a noveltablet structure and relates more particularly to a method for thepreparation of a unitary pharmaceutical tablet structure formed of aplurality of separable sections normally joined to each other in suchmanner that the sections may readily be separated from each other by theapplication of a moderate manual pressure.

An object of this invention is the provision of a unitary pharmaceuticaltablet normally constituting a single dosage unit but formed of sectionswhich may be accurately divided and conveniently separated intoindividual dosage units.

Another object of this invention is to provide a method for thepreparation of a readily divisible compressed tablet of novelconfiguration and composition which has a low bulking factor and whichis adapted to nest readily in a container on random fill.

A further object of this invention is to provide a method for thepreparation of a unitary compressed tablet structure which is suitablysectioned and which is adapted to be further processed by film coatingor other tablet surface coating without impairing the ease andreliability with which said sectioned tablet structure may be subdividedinto plurality of dosage units.

Other objects will appear from the following detailed description of thepresent invention.

Compressed tablets are widely employed'as a means of marketing manyproducts in the drug industry where individual dosage units are desired.To form tablets, a suitable, freely-flowing granulation is prepared andfed to a tablet press. The press may operate with a single set ofpunches, or a high speed rotary tablet press may be employed where alarge series of punches operate on a high speed rotary bed. The shape ofthe surfaces of the punches or dyes between which the granulation iscompressed determines the shape of the tablet which is formed and aninfinite variety of shapes and monogrammed surfaces may be obtained.Aside from variations in the peripheral shape of such compressedtablets, these tablets, most commonly, are either flat-faced or haveslightly convex surfaces. For ease of subdivision, may tablets arecentrally scored across one surface. An example of such a tablet is thatdisclosed in the Wilhelm patent, US. Pat. No. 2,386,416. In the case ofsmall and moderately thick tablets formed of granulations containingappreciable quantities of waxy or wax-like diluents, scoring 1 proves oflittle advantage since such diluents tend to produce strong and hardtablets which are rather brittle. Such tablets are not very amenable tosubdivision by ordinary manual pressure, and usually are difficult tobreak for purposes of obtaining a predetermined fractional dosage.Hence, where several different dosage schedules may be recommended to apatient, the difiiculty of subdividing these tablets to follow suchschedules may require the production of several different tablet sizesrather than the production of one size which can be conveniently andaccurately subdivided into fractional dosage units. Where the originalcompressed tablets require a film or othersuitable coating in order toproduce a technically satisfactory as well as a pharmaceuticallyacceptable product, such coatingstend to obliterate any 3,336,200Patented Aug. 15, 1967 scoring to such a degree that the subdivision ofa large coated tablet into subdivided dosage forms is quite impracticaland unsatisfactory.

In accordance with the present invention, there is now provided a methodfor the preparation of an improved pharmaceutical tablet of a new andnovel structure, which can be readily formed by compression, asdescribed, in either a coated or an uncoated form and which may easilybe subdivided into a plurality of dosage units by the simple applicationof a moderate manual pressure. The present invention is more clearlyillustrated by the accompanying drawing in which there is shown severalmodifications of the improved tablet structure of this invention.

In the drawing:

FIG. 1 is a view in perspective of a tablet structure of this inventionhaving one of the two faces formed of angularly disposed surfaces withthe other face being a fiat surface lying in a single plane, and

FIG. 2 is a view in perspective of a tablet structure of this inventionin which each of the two faces comprises a plurality of surfacesangularly disposed with respect to each other, and

FIG. 3 is a further modification of the tablet structure of thisinvention wherein the tablet may be subdivided into more than twosections.

Like numerals indicate like parts in the several views of the drawing. 1

Referring now to the drawing, and more particularly to FIG. 1, thetablet structure shown comprises a lower face 5 and an upper face 6divided into sections 7 and 8. As shown each of sections 7 and 8 lie inseparate planes .which intersect along a line 9 and form an angle A intercepting an arc of less than 180 and preferably an arc of about toabout The material forming the tablet structure is thicker at the sidesthan it is at the center and the thinnest portion lies along the line 9where the surfaces of sections 7 and 8 intersect. Line 9 may be definedmerely by the intersection of the surfaces of sections 7 and 8 or it maybe defined by providing a somewhat deeper score line, as shown. In orderto subdivide the unitary tablet structure and to separate it intoindividual dosage units a moderate manual pressure is applied to theupper and lower faces of the tablet by means of the thumb andforefinger. The leverage exerted on the separate sections of the upperface has its fulcrum along line 9 and since the thinest portion of thetablet lies along line 9 it is easily broken there thus forming twoequal halves.

While the tablet structure shown in FIG. 1 is of unequal thickness fromthe edges to the center, the tablet may also be of uniform thickness asshown in FIG. 2. In this modification both the upper face 10 and thelower face 11 are formed of separate sections, the upper face 11consisting of sections 12 and 13 lying in separate planes whichintersect along a line 14. The lower surface 11 is similarly formed ofseparate sections the surfaces of which lie parallel to the surfaces 12and 13, respectively, and which meet along a line 15 on the lower faceof the tablet structure. Line 14 may comprise a somewhat deeper scoreline, if desired. The tablet structure shown in FIG. 2 is readilysubdivided into separate dosage units merely by placing the tabletbetween the thumb and forefinger and by applying manual pressure. Theleverage exerted by pressure upon the sections of the upper face causethe tablet to split readily along line 14 and to yield equal halvesforming separate dosage units.

The tablet structure shown in FIG. 3 enables a single dosage unit to besubdivided to form either two or four separate dosage units. In thisstructure the upper face of the tablet 16 is divided into separatesections 17, 18, 19 and 20, respectively, with the surfaces of sections17 and 20 lying in one plane and the surfaces of sections 18 and 19lying in another plane, each of said planes being at an angle to eachother embracing an arc of less than 180 and meeting in a line 21. Inthis respect tablet 16 is similar to that shown in FIG. 1 and maysimilarly be subdivided into two separate units along line 21 by theapplication of manual pressure. However, in order to enable tablet 16 tobe further subdivided additional scoring is provided to separate thesurface of section 17 from the surface of section 20 and similarly, thesurface of section 18 from the surface of section 19 thus forming spaces22 and 23 which may be joined at the base of the tablet (not shown) ormerely be open.

The novel tablet structures of this invention are especially valuablefor use where the tablets contain therapeutic agents together with asubstantial amount of a wax or similar diluent in order to obtain atimed and sustained release of the active ingredient since a substantialproportion of waxes in the tablet composition tends to form a very hardand brittle tablet which is diflicult to subdivide when formed into theusual shapes. For example, when an ordinary flat-faced sugar tablet isformed by compression of 400 milligrams of sugar to a thickness of0.160" and a diameter of with a score line on the top and bottomsurfaces, such a tablet will easily fracture since it will have anaverage hardness of less than about 6 to about Strong-Cobb units asmeasured on a tablet hardness testing machine customarily used fordetermining the hardness or resistance to crushing of pharmaceuticaltablets. An example of such a testing machine which has been widelyadopted in the art is described in Albrecht U.S. Patent No. 2,645,936.In contrast, a tablet of similar size and construction formed of acomposition having a substantial quantity of waxy fillers or diluentstherein may have an average hardness of about to about 25 Strong-Cobbunits, which makes it extremely difficult, if not impossible, tofracture with manual pressure exerted solely by ones fingertips. A waxyfilled tablet formed by the present structure, however, may be readilyfractured into equal dosage units by a moderate finger pressure.Although the present structure may be employed in construction ofrelatively soft tablets such as those having a Strong-Cobb hardness ofless than about 10, it finds its greatest utility in application tothose tablets having a Strong-Cobb hardness of greater than about 12 toabout 15, which tablets may not be easily fractured into separate dosageunits when in the shape of conventional tablets.

In order further to illustrate this invention, the following examplesare given:

EXAMPLE 1 A granulation is prepared of the following components.Ingredient: Parts by wt. Carnauba wax 4 Stearic acid l6Phenylpropanolamine hydrochloride 10 Lactose 50 Color 0.03

The carnauba wax is melted at 85 C. and the stearic acid is then addedto the molten solution. The phenylpropanolamine hydrochloride andlactose are then added to the molten mixture obtained after which asolution of the color in a small amount of water is also added. The massis mixed until uniform and allowed to solidify in trays. Aftersolidification, the mix is granulated by being passed through a mill.

A second granulation is prepared from the following components.

Ingredient: Parts by wt. Polyethylene glycol 4000, USP 4 LactosePhenylpropanolamine hydrochloride 5 Color 0.005 Magnesium stearate 0.2

The polyethylene glycol is heated to 70 in a suitable mixer. The lactoseand the phenylpropanolamine hydrochloride are then slowly added to thepolyethylene glycol. The color is next dissolved in 1.66 parts by weightof water and added as a solution, with mixing, to the other ingredients.After a substantially uniform blend is obtained, the mixture istransferred to trays where it is allowed to solidify. The solidifiedmaterial is then milled to form a granulation with which the magnesiumstearate is uniformly blended.

The separate granulations are then compressed into double layer tabletswhose layers are of substantially uniform thickness, each tabletweighing about 705 milligrams, the bottom layer (first granulation)weighing up to about 485 milligrams. The punches employed are shaped toproduce a center scored tablet in which the two halves of the tabletwhich meet along the score line are at an angle of 135 to each other.The tablets obtained even though the bottom layer is of a hard, waxystructure may easily be divided into two halves by exerting manualpressure on the tablet with the forefinger so as to divide it intoseparate dosage units. The tablets are found to have an average hardnessof about 18 Strong-Cobb units.

EXAMPLE 2 A sustained release and an immediate release granulation areeach prepared in the following manner:

Sustained aclion' granulation Eight parts by weight of carnauba wax areheated at C. in an agitator and 32 parts by weight of stearic acid areadded and mixed until a uniform melt is obtained. To this melt is thenadded 50 parts by weight of phenyltoloxamine dihydrogen citrate and 70parts by weight of lactose. After the melt has been uniformly mixed, 6.5parts by weight of phenobarbital are added followed by a solution of0.033 part by weight of FD & C Yellow No. 5 in 0.8 part by weight ofwater. The waxy mixture is then spread in thin layers on drying traysand broken up into small particles after hardening. The mixture is thenmilled to granular form and blended with 1.3 parts by weight ofmagnesium stearate.

Immediate release granulation 7.33 parts by weight of polyethyleneglycol 4000 are heated to 70 C. 60 parts by weight of lactose, 3.33parts by weight of phenobarbital and 10 parts by weight ofphenyltoloxamine dihydrogen citrate are then gradually added to theheated polyethylene glycol. To this mixture is added, 0.003 part byweight of PD & C Yellow No. 5 in 3.33 parts by weight of water. Theuniform mixture obtained is then placed on drying trays and aftersolidification the mixture is milled to a granular form. 0.3 part byweight of magnesium stearate is then thoroughly blended with thisgranulation. The immediate release granulation and the sustained releasegranulation are then compressed into V-shaped double layer tabletsweighing about 753 milligrams, with the sustained action layer weighingabout 524 milligrams. The tablets are formed to a general V-shape tabletbetween suitably shaped punches yielding tablets of uniform thicknesswhose sides meet at an angle of about In this composition the sustainedrelease layer constitutes a hard, waxy formulation, yet the tablet mayeasily be subdivided into two equal parts by pressure of the forefinger.The tablets so formed are found to have an average hardness of about 16Strong- Cobb units.

EXAMPLE 3 The following separate granulations are prepared in the mannerdescribed above.

Ingredient: Parts by wt. Phenylpropanolamine hydrochloride 2.5 Ephedrinehydrochloride 7.5 Sodium butabarbital 12 Starch Lactose 20 Stearic acidpowder 3.5 Polyethylene glycol 6000 3 Phenylpropanolamine hydrochloride37 Stearic acid powder 24 Ethyl cellulose .5 Carnauba wax 2.5 Sugar 26FD & C Red No. 4 0.08 FD & C Red No. 2 0.1 Water 1 Ephedrinehydrochloride 65 Stearic acid powder 17 Camanba wax 14 Ethyl cellulose 4Magnesium stearate 1 PD & C Red No. 4 0.03 Water 1.7

Granulations B and C are mixed and this mixture is then compressed withgranulation A into double layer tablets weighing about 450 milligrams,the top layer being granulation A with the bottom layer weighing about240 milligrams. The overall tablet thickness is about 0.23 inch and thetablet so formed is generally of the V-shape tablet wherein the thicksides meet at the center at an angle of about 135. The lower orsustained release waxy layer, although quite hard, is readily divisibletogether with the upper immediate release layer by merely exertingpressure on the tablet by the forefinger. The tablet is found to have anaverage hardness of about 15 Strong-Cobb units.

It is understood that the foregoing detailed description is given merelyby way of illustration and that many variations may be made thereinwithout departing from the spirit of our invention.

What is claimed is:

A compressed V-shaped center scored double layer tablet, having a drugin two separate granulations, comprising:

(a) an immediate release drug granulation of a drug in tabletgranulation excipients and lubricant in the upper layer, and

(b) a sustained release drug granulation of the same drug in carnaubawax and stearic acid with tablet granulation excipients in the lowerlayer, said separate immediate and sustained release drug granulations,of the same drug, having been compressed into V-shaped center scoreddouble layer tablets having an average hardness of about 15-18Strong-Cobb units and layers of substantially uniform thickness, whereinthe two top halves constituting the upper plane surfaces of the tabletsare joined at the center score at an angle of about to each other sothat the application of a unidirectional finger pressure exerted on thecenter of the lower face of the tablet placed with the upper face downon a firm surface causes the tablet to split into two equal halves, eachhalf containing predetermined fractional dosages of the same drug inboth an immediate release drug granulation and in a sustained releasedrug granulation.

References Cited UNITED STATES PATENTS D 91,644 3/1934 Blackstone 1632,082,312 6/1937 Todd 99-138 2,082,313 6/1937 Todd 99l38 2,798,4437/1957 Martell l071 2,809,917 10/1957 Hermelin 167-82 2,887,438 5/1959Cooper et al. 16782 2,951,792 9/1960 Swintosky 16782 3,048,526 8/1962Boswell 167--82 3,145,146 8/1964 Lieberman et al. 167-82 D 201,497 6/1965 Ninger 16-3 D 202,467 10/1965 Guilmot 16--3 FOREIGN PATENTS 352,2089/1937 Italy. 808,014 1/1959 Great Britain.

OTHER REFERENCES Atlas Pharmaceutical Bulletin, A Guide to Using AtlasMannitol, N.F., as a Base in Press-Coated and Multi- Layer Tablets, 12pp. August 1959.

Tsevdos: Press-Coated and Multi-Layer Tablets, Drug & Cosmetic Industry78 (1), pp. 38-40, 113-114, January 1956.

LEWIS GO'ITS, Primary Examiner.

S. K. ROSE, Assistant Examiner.

